Researchers Engineer Immune Therapy to Harness the Body’s Natural Regulatory Pathways to Promote Transplant Tolerance

Organ transplantation has transformed the lives of millions of patients with end-stage organ failure. Yet long-term success remains limited by the need for lifelong immunosuppressive medications, which can cause serious complications including kidney toxicity, diabetes, hypertension, infections, cancer, and neurologic side effects. In a preclinical study published in Nature Communications, investigators from Mass General Brigham and collaborators developed an engineered interleukin-2 (IL-2) therapy that harnesses the body’s own immune regulatory mechanisms to promote transplant tolerance. The approach selectively expands regulatory T cells—the immune system’s natural “brakes”—allowing the immune system to accept transplanted organs while preserving broader immune function.

“For decades, transplantation has relied on broadly suppressing the immune system to prevent rejection,” said corresponding author Leonardo Riella, MD, PhD, of the Center for Transplantation Sciences and the Division of Nephrology at Mass General Brigham. “Our goal is fundamentally different. We are leveraging the body’s own immune regulatory pathways to teach the immune system to accept a transplanted organ. If successfully translated to patients, this strategy could reduce the need for lifelong immunosuppression and many of its associated toxicities.”

The therapy developed by the researchers is based on a modified form of interleukin-2 (mIL-2), a naturally occurring immune signaling molecule. Unlike conventional immunosuppressive drugs, which broadly inhibit immune responses, mIL-2 was engineered to selectively expand regulatory T cells (Tregs), a specialized population of immune cells responsible for maintaining immune tolerance and preventing inappropriate immune attacks. By enhancing these natural regulatory pathways, the therapy promotes donor-specific immune regulation rather than generalized immune suppression.

Using mouse models of heart and kidney transplantation, the researchers found that mIL-2 significantly prolonged graft survival and, when combined with a single dose of immunosuppression at the time of transplantation, induced long-term acceptance of transplanted organs even after treatment was discontinued. Mechanistic studies demonstrated that the therapy expanded a specialized subset of regulatory T cells associated with transplant tolerance while selectively suppressing immune responses directed against donor tissues. Importantly, the findings suggest the possibility of achieving durable immune acceptance through immune reprogramming rather than continuous pharmacologic suppression.

“The ultimate goal in transplantation is tolerance—the ability for a recipient to accept a transplanted organ without requiring lifelong immunosuppression,” Riella said. “While additional studies are needed, these findings provide proof-of-concept that we may be able to harness the immune system’s own regulatory circuits to achieve long-term graft acceptance with fewer of the complications associated with current immunosuppressive therapies.”

Authorship: In addition to Riella, Mass General Brigham authors include Yoshikazu Ganchiku, Guilherme T. Ribas, Karina Lima, Rodrigo B. Gassen, Kaifeng Liu, Orhan Efe, Jason W. Griffith, Andrew D. Luster, Ivy A. Rosales, Christian LeGuern, and Thiago J. Borges. Additional authors include Zachary Shriver and Gregory J. Babcock.

Disclosures: The authors declare that they have no competing interests.

Funding: This work was supported by Visterra Inc., the American Heart Association (grant 23CDA1049388), Department of Defense (grant W81XWH-21-1-0904), and the National Institutes of Health (grant R01AI143887).

Paper cited: Ganchiku Y et al. “IL-2 Mutein Promotes Antigen-Specific Transplant Acceptance through Expansion of Transplanted ST2+ Regulatory T Cells.” Nature Communications DOI: 10.1038/s41467-026-74185-8